Gut 1995; 37: 477-481

Omeprazole enhances efficacy of triple therapy ineradicating Helicobacter pyloni

T J Borody, P Andrews, G Fracchia, S Brandl, N P Shortis, H Bae

AbstractTriple therapy has been recommendedas the most effective treatment forHelicobacter pylori eradication. Despiteachieving a comparatively high eradica-tion result, however, around 10% ofpatients still fail to be cured. Omeprazolecan enhance efficacy of single and doubleantibiotic protocols and is particularlyeffective when combined with clarithro-mycin and a nitroimidazole. This studyexamined the effect of combining tripletherapy with omeprazole. A prospective,randomised, unblinded, single centretrial was carried out on consecutivepatients with symptoms of dyspepsia andH pylori infection confirmed by rapidurease test, microbiological culture, andhistological assessment. Patients weregiven a five times/day, 12 day course ofcolloidal bismuth subcitrate chewabletablets (108 mg), tetracycline HCI(250 mg), and metronidazole (200 mg)with either 20 mg omeprazole twice daily(triple therapy+omeprazole) or 40 mgfamotidine (triple therapy+famotidine)at night. Compliance and side effectswere determined using a standard ques-tionnaire form. One hundred and twentyfive of 165 triple therapy+omeprazolepatients and 124 of 171 tripletherapy+famotidine patients returnedfor rebiopsy four weeks after completionof treatment. Significantly more tripletherapy+omeprazole patients achievederadication 122 of 125 (97.6%) as assessedby negative urease test, culture, andhistological assessment, when comparedwith 110 of 124 (89%) tripletherapy+famotidine patients (p=0.006;x2). There were 30 triple therapy+omeprazole (24%) and 26 triple ther-apy+famotidine (21%) patients with denovo metronidazole resistant H pylonincluded in the study. Side effects weremild and infrequent and were compar-able in both groups, although pain induodenal ulcer, gastric ulcer, andoesophagitis patients seemed to subsideearlier in those taking omeprazole.Compliance (>95% of drugs taken) wasachieved by 98% of patients of bothgroups. A 12 day regimen of tripletherapy with omeprazole is more effec-tive in achieving H pylon eradicationthan is triple therapy plus famotidine.Use of 20 mg omeprazole twice dailyrather than 40 mg famotidine with a 12day, low dose triple therapy enhanceseradication to over 97%/o whether the

H pylon is metronidazole sensitive orresistant.(Gut 1995; 37: 477 -481)

Keywords: Helicobacter pylon, omeprazole, eradication.

Eradication of Helicobacter pylori is of import-ance in achieving a cure of duodenal andgastric ulcer disease. However, the ideal thera-peutic regimen for its eradication remainselusive. Triple therapy, using bismuth sub-citrate, metronidazole, and tetracycline oramoxycillin achieves the highest eradicationresultsl and has therefore been recommendedas the preferable treatment for ulcer disease.2Even with this combination of three drugsactive against H pylori, around 1 0% of patientsfail to be cured of the infection.3 The reasonsfor failure are unclear, but compliance andmetronidazole resistance are thought to be ofimportance.3When studying H pylori eradication in

patients in whom seemingly adequate treat-ment with triple therapy had failed to cure theinfection,4 we found that addition ofomeprazole to triple therapy (quadrupletherapy) cured overall 78% of those infected.Furthermore, addition of omeprazole tomonotherapy, such as amoxycillin, was knownto improve H pylori eradication with successranging from 30-80%. The few studies avail-able on omeprazole combined with dualtherapy also suggest eradication enhancementranging from 43% to over 90%.1 2 6-10 Studiescombining omeprazole with triple therapy asfirst line of treatment have suggested consis-tently high eradication in excess of 90/oO.ll 12There has been no formal prospective work,however, to look for any positive contributionthat omeprazole might give to the already higheradication rates achieved by triple therapycurrently given with H2 receptor antagonists.In this study we examine the effect of addingomeprazole to triple therapy and contrastthis with the addition of famotidine to tripletherapy, which is used routinely in ourstandard clinical protocol.

Methods

PatientsThe study was a prospective, randomised,unblinded, single centre trial carried out onpatients with dyspepsia referred to the Centrefor Digestive Diseases. Dyspepsia symptomsincluded epigastric pain or discomfort, nausea,vomiting, eructation, bloating or heartburn.Patients were included in the study ifH pylori

Centre for DigestiveDiseases, Five Dock,NSW, AustraliaT J BorodyP AndrewsG FracchiaS BrandlN P ShortisH Bae

Correspondence to:Dr T J Borody, Centre forDigestive Diseases, 144Great North Road, FiveDock, NSW 2046, Australia.

Accepted for publication16 February 1995

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eradication was clinically judged to be ofbenefit to the patient. A proportion of thepatients suffering from non-ulcer dyspepsia oroesophagitis in whom other treatments hadfailed were included in the study as there is pre-liminary evidence that in subgroups of suchcategories symptomatic benefit can occur.13 14Another significant subgroup of patients hadbeen diagnosed previously as having radio-logically or endoscopically confirmed ulcerdisease but were currently endoscopically freeof ulcers or scarring. All patients gave theirinformed consent to be included in the study,which was conducted in accordance with therevised Declaration of Helsinki15 and wasapproved by the ethics committee of the Centrefor Digestive Diseases. Patients were excludedfrom the study if they had previously failed anyH pylori therapy, on the assumption that theybelonged to the 'eradication failure' category.4

H pylori statusPresence of H pylori infection was assessedendoscopically in every patient by rapid ureasetest, histological examinations, and microbio-logical culture of gastric biopsy specimensobtained before the treatment and four weeksafter completion of triple therapy. All examina-tions were performed by the same endoscopist(TJB) with the specimens taken from thegastric antrum and body. The methods usedhave been described previously16 17 and will besummarised here. One antral specimen wasplaced in a microtitre tray, which containedbuffered urea and an indicator for rapiddetection of urease activity as previouslydescribed.18 Two antral specimens were takenfor microbiological culture, which in our handsis the most sensitive method of detecting thepresence ofH pylori 16 17 One antral and onegastric body specimen was placed in 10%buffered formalin for histological examinationcarried out using a modified Giemsa stain. Theresults were considered Hpylori positive if anyone of the three tests used (rapid urease,microbiology or histology) showed evidence ofH pylori infection. Metronidazole resistancewas determined on chocolate agar by compara-tive disc diffusion (50 ,ug concentration) usingNCTC 1 1639 reference H pylori strain.Resistance was deemed present with a zone ofinhibition of less than 5 mm.

TreatmentPatients were given a triple therapy regimenconsisting of chewable colloidal bismuth sub-citrate (De Nol; 108 mg), tetracycline HCI(250 mg), and metronidazole (200 mg) fivetimes per day20 (7 am, 11 am, 3 pm, 7 pm,11 pm) for 12 days with either omeprazole(20 mg) at 7 am and 7 pm or famotidine(40 mg) at 11 pm only. The omeprazole dosewas chosen to be equivalent to that usedin the omeprazole-amoxycillin trials.21 Thefamotidine 40 mg night time dose hadreplaced ranitidine as our standard H2 receptorantagonist combined with triple therapy.20 Atleast four weeks after the completion of triple

therapy (mean (SD) 33-8 days) patients hadanother biopsy to assess H pylori eradication.Urease test, histological assessment and cul-ture were again used to detect evidence ofHpylori infection.

Compliance and side effectsTo obtain high eradication we endeavoured tomaximise patient compliance by educating andtraining the patients in taking the drugs withwhich considerable experience had beenaccumulated at the centre.22 Verbal explana-tions and printed instructions were given to thepatient. These emphasised that a totally com-pliant 'first time therapy' would guarantee anear 100% cure while retreatment could resultin a considerable fall in eradication success.To assess compliance, patients filled out astandard questionnaire and were interviewedat the six week visit. This has been a successfultool in our hands as measured by eradicationsuccess. Patients were asked to grade the sideeffects of nausea, vomiting, abdominal pain,oral discomfort, diarrhoea, constipation, andrash from nil to severe. Scores were assignedaccording to severity in the following way: nil,score 0; no side effects experienced: mild,score 1; effects seen but could be disregarded:moderate score 2; effects bad enough to calldoctor but could continue treatment andtolerate discomfort: severe, score 3; effectsinterfered with activities at work; side effectshad to be treated or triple therapy had to bediscontinued. In practice, a score of 1 wasassigned to patients who did not recall sideeffects when asked 'did you have any sideeffects?' but who recalled experience of sideeffects when confronted with a list ofindividual side effects. A score of 2 or morewas given when patients could recall sideeffects without prompting. For this reason,only scores of 2 or 3 were included as 'clinicallysignificant side effects'.

Statistical analysisH pylori eradication for the triple therapyregimens with famotidine and omeprazole wascompared using the x2 test. The differencesbetween mean values of side effects' severity inthe two groups and mean number of dosesmissed by non-compliant patients were deter-mined by Student's t test. All values withp<005 were considered to be statisticallysignificant.

ResultsA total of 165 and 171 patients were randomlyassigned to the triple therapy plus omeprazoleand triple therapy plus famotidine groupsrespectively. One hundred and twenty fivepatients returned following the triple ther-apy+omeprazole regimen (75.8%) and 124patients who received triple therapy+famoti-dine regimen (72.5%), four weeks after com-pletion of treatment.

Despite a complete phone follow up andremuneration offer a significant number of

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Optimal H pylori therapy

TABLE I Demographic data ofpatients included in thestudy

Tnple therapy+ Tiple therapy+oineprazole famotidine

Number 125 124Mean age (SD) 51-4 (12-8) 52.5 (15.5)Male/female 60/65 67/57Eradication of H pylori (%) 122/125 (97.6) 110/124 (89)DiagnosisDuodenal ulcer 38 34Gastric ulcer 5 3Non-ulcer dyspepsia 50 37Oesophagitis 22 23Other (past history of ulcer) 11 21

Some patients had multiple diagnoses.

patients could not be induced to undergo thesecond endoscopy, often for a variety ofeconomic reasons including preservation ofemployment status. In addition, as in our pre-vious studies, most (64% of those contacted)claimed they were feeling well and did notwish to proceed with the re-endoscopy.Symptomatic patients were more interested tosee whether they still carried the infection20 23and returned more frequently for rebiopsy.The bias in the study was therefore towards theH pylori positive patients returning with a pre-sumed equivalent 'loss to follow up' occurringin each of the study arms.Of the patients who returned for re-

endoscopy 111 in the triple therapy+omeprazole group and 103 in the triple ther-apy+famotidine group filled out side effectquestionnaire forms. Demographic data andpredominant endoscopic diagnosis for allpatients included in the analysis of the studywas listed. There were no significant demo-graphic or diagnostic differences between thegroups of patients using triple therapy witheither omeprazole or famotidine (Table I).

H pylori eradicationH pylori was judged to be eradicated in 122 of125 (97.6%) patients using the triple ther-apy+omeprazole regimen. Conversely, 1 10 of124 (89%) patients were cured ofHpylori usingtriple therapy+famotidine regimen. All threetests used, urease, histological assessment, andmicrobiology, had to be negative to considerH pylori as being eradicated. There was asignificant statistical difference found betweenthese eradication results (p=0-006; X2). Theinitial sample (165 triple therapy+omeprazoleand 171 triple therapy+famotidine patients)would have provided more than 80% power(the usual value used) to the study but the dropout rate was higher than expected so that in theend the power was 70%. Statistically significant

TABLE II Comparison of side effects between triple therapy plus omeprazole (TT+ 0) andtriple therapy plus famotidine (TT+F), either as scores or absolute values

Clinically significantMean (SEM) score side effects (%o)

Symptoms TT+0 TT+F p Value TT+0 TT+F p Value

Nausea 0-36 (0.07) 0-42 (0.06) 0.5 7-2 12-6 0-18Vomiting 0.07 (0.04) 0.07 (0.03) 1 1-8 1-9 0-94Abdominal pain 0.25 (0.05) 0-21 (0.04) 0.54 2-7 1.9 0.71Oral discomfort 0.24 (0.06) 0-25 (0.05) 0.9 5 4 6-8 0-67Diarrhoea 0.13 (0.04) 0.13 (0.04) 0.87 1.8 1.9 0 94Constipation 0.06 (0.03) 0.05 (0.02) 0.78 0.9 0.9 0-96

results were found, however, and there was a70% chance of finding them if they werepresent.

Side effectsSeverity of side effects experienced by thepatients in the two groups was compared.Table II lists the frequencies of side effectswith the most frequent being nausea, occurringin 7.2% (triple therapy+omeprazole) and12.6% (triple therapy+famotidine) patientsfollowed by oral discomfort in 5.40/o and 6.8%,presumed to be caused by transient oral can-didiasis. Patient compliance did not seem to beaffected by these usually minor side effects.Furthermore, there was no statistically signifi-cant difference in scores for nausea, vomiting,abdominal pain, oral discomfort, diarrhoea orconstipation between the two groups.Although not measured by the questionnaire,there was a distinct clinical impression thatdyspeptic symptoms, especially abdominalpain, abated more rapidly in patients usingomeprazole.

ComplianceBased on self reporting, 970/o of patients in thetriple therapy+omeprazole group and 96% ofthose treated with triple therapy+famotidinewere '100% compliant' with the treatment.There was no statistical difference between thetwo results (p=0.628).

Metronidazole resistanceDe novo metronidazole resistance was foundto be present in 24% of patients in the tripletherapy+ omeprazole and 2 1/% triple therapy+famotidine groups. Using the culture method-ology described and particularly that of placinggastric biopsy specimens directly onto theculture plate from the biopsy forceps, H pylorigrowth was obtained in all patients studied.Although it is recognised that in many centresH pylori culture is achieved in no more than80% of instances as it was in the early days inour laboratory, our current success rate in over8000 patients approaches 98%.l7 Of the threepatients who failed to eradicate Hpylori in thetriple therapy+omeprazole group one of threewas metronidazole resistant, another hadrecently (within the past four weeks) taken acourse of amoxycillin, while the last wasincompletely compliant to the treatment.

DiscussionThis study describes the use of triple therapycombined with omeprazole for 12 days. Whenused in compliant Australian patients this pro-tocol approaches 100% (97.6%) eradication.Other clinicians have reported such a combi-nation to be highly efficacious. Hosking et al, 1 1in Hong Kong, using only 20 mg omeprazolein the morning together with colloidalbismuth subcitrate, tetracycline 500 mg, andmetronidazole 400 mg four times daily (n=78)achieved eradication in 95%/n of patients using

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only a seven day course. This group subse-quently published another, similar study,which resulted in 98% eradication.24 InAustralia, with a smaller patient group (n= 25),Daskalopoulos et a112 used a 14 day courseof omeprazole 20 mg/day with colloidal bis-muth subcitrate, tetracycline 250 mg, andmetronidazole 200 mg four times daily, achiev-ing 96% (24 of 25) eradication. Such resultscorroborate our 97.6% result carried out in alarge patient cohort, using lower treatmentdoses. Our patients took 750 mg lesstetracycline and 600 mg less metronidazole perday though omeprazole was 20 mg twice dailyv 20 mg/d. A further finding of this study is thehigher H pylori eradication by triple therapyachieved by substituting 40 mg omeprazole for40 mg famotidine. This finding suggests thatomeprazole indeed contributes to the improve-ment in eradication.

Although this protocol may seem cumber-some it works well in clinical practice perhapsbecause it is brief. Furthermore it is feasible tocombine the three components of triple ther-apy into a fixed dose combination therapy as asingle tablet. This would simplify dosing andenhance compliance. In view of the 95%eradication obtained by Hosking et al1 1 using aseven day protocol it seems probable that asingle tablet could be given for only seven dayswithout significant loss of efficacy and perhapswith further reduction in component doses oftriple therapy. Indeed, a one day triple therapy(CBS 240 mg X4; amoxycillin 2 g X4;metronidazole 500 mg X 4) with 40 mgomeprazole, has achieved an eradication of72%.25 Therefore, there seems to be scope forthe reduction not only of triple therapycomponent doses but also for the reduction intreatment duration.The use of a simplified protocol using

omeprazole and amoxycillin has recentlyattracted much interest. Variable and oftenconflicting eradication results have emerged,however, ranging from 28-82%. This ledCollins et al 5 to conclude that 'based onpresent evidence, omeprazole and amoxycillincannot yet be considered the optimal regimenfor eradicating H pylori'. The best of the latestpublished protocols using the dual therapyachieves an 80-82% eradication in a popu-lation selected out for penicillin sensitivepatients.23 26 This selection further reduces theeradication to <80% when considering 'allcomers'. The major restriction of amoxycillincontaining eradication therapies is the exist-ence of penicillin sensitivity in a significantproportion of the population, which willprevent eradication ever approaching 100%described here. Tetracycline containing tripletherapy does not suffer from this disadvantageand is therefore amenable to further optimisa-tion.

Side effects of triple therapy have been usedas an argument to develop alternativeprotocols.26 Side effects of triple therapy aregenerally minor, however,2S28 reduced by thelower dose triple therapy recently intro-duced,20 and clinically have been found to beno different by some to side effects of

omeprazole alone. 1" In this study the combina-tion of five times/day triple therapy withomeprazole resulted in infrequent, mild, andcertainly clinically insignificant level of adversereactions. Though not measured directly, itwas our impression that the addition ofomeprazole shortened duration of dyspepticsymptoms in those patients with ulcers andreflux symptoms.

In vitro metronidazole resistance ofH pyloniis currently being invoked as perhaps the majorobstacle to more successful eradication whenusing triple therapy.5 27 29 30 Metronidazoleresistance therapeutic studies, however, haveyet to differentiate between patients with denovo and post therapy metronidazole resis-tance.28 31 Indeed, when compliant patientpopulations with and without de novometronidazole resistant bacteria are compared,Hpylorz eradication with triple therapy is virtu-ally equivalent.19 On the other hand, there isgeneral agreement that after failed antibiotictreatment H pylori becomes less responsive tore-treatment and even complex antibiotic com-binations achieve but modest eradicationresults6 32 33 suggesting that prior, recentexposure to antibiotic treatment or toomeprazole,34 may be the major cause of sub-sequent eradication failure. In fact in vitro'metronidazole resistance' can develop withoutmetronidazole use35 and rather than achievinghigh eradication, metronidazole free tripletherapy (bismuth subcitrate, amoxycillin,tetracycline) has achieved a mere 20%success.36 It is therefore of clinical importancethat addition of twice daily omeprazole totriple therapy can virtually remove the per-ceived problem of metronidazole resistance.With a de novo, in vitro resistance status of24% in our triple therapy+omeprazole groupand H pylori eradication rates of 97.6%metronidazole resistance seems to be of noclinical relevance. Such also were the findingsof Hosking et al24 who achieved 98% eradica-tion in his group of patients despite 48%metronidazole resistance.

In conclusion, a 12 day course of lower dosefive times/day triple therapy combined with 20mg twice daily omeprazole seems to be anefficient protocol achieving, in unselectedpatients, an eradication of H pylori of97.6% whether it be resistant de novo tometronidazole or not. The high eradicationmay permit further reduction of triple therapycomponent dose and a shorter duration oftreatment without loss of efficacy.

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2 Axon ATR. Helicobacter pylori therapy: effect on pepticulcer disease. Jf Gastroenterol Hepatol 1991; 6: 131-7.

3 Ruaws EAJ. Reasons for failure of Helicobacter pylori treat-ment. European Journal of Gastroenterology and Hepatology1993; 5 (suppl 2): S92-5.

4 Borody TJ, Brandl S, Andrews P, Jankiewicz E, OstapowiczN. H pyloni eradication failure (EF) - further treatmentpossibilities. Gastroenrerologry 1992; 102: A43.

5 Collins R, Beattie S, Xis HX, O'Morain C. Short report:high-dose omeprazole and amoxycillin in the treatment ofHelicobacter pylori-associated duodenal ulcer. AlimentPharmacol Ther 1993; 7: 313-5.

6 Al-Assi MT, Genta RM, Graham DY. Failure of omepra-zole to enhance antimicrobial therapy for H pyloni:omeprazole with tetracycline or tetracycline and bismuth.AinJ Gastroenterol 1993; 88: 1502.

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7 McCarthy CJ, Collins R, Beattie S, Hamilton H, O'MorainC. Short report: treatment of Helicobacter pylori-associ-ated duodenal ulcer with omeprazole plus antibiotics.Aliment Pharmacol Ther 1993; 7: 463-6.

8 Bell GD, Powell KU, Burridge SM, Rameh B, Bolton G,Purser K, et al. Helicobacter pylori eradication: a combi-nation of omeprazole, amoxycillin and metronidazolecompared with standard triple therapy. Gut 1993; 34(suppl 1): S37.

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10 Bazzoli F, Zagary RM, Fossi S, Pozzato P, Roda A, Roda E.Efficacy and tolerability of short term low-dose tripletherapy for eradication of Helicobacter pylori.Gastroenterology 1993; 104: A40.

11 Hosking SW, Ling TKW, Yung MY, Cheng A, ChungSCS, Leung JWC, et al. Randomised controlled trial ofshort term treatment to eradicate Helicobacter pylori inpatients with duodenal ulcer. BMJ3 1992; 305: 502-4.

12 Daskalopoulos G, Carrick J, Lian R, Lee A. Optimisingtherapy for .H pylori gastritis. Ir J Med Sci 1992; 166(suppl 10): 16.

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14 O'Morain C. Helicobacter pylori and non-ulcer dyspepsia.Gastroenterology 1992; 103: 340-7.

15 World Medical Assembly. The Declaration of Helsinki.World Med J 1982; 29: 86-8.

16 Borody TJ, George LL, Brandl S, Andrews P, OstapowiczN, Hyland L, et al. Helicobacter pylori-negative duodenalulcer. Am J Gastroenterol 199 1; 89: 1154-7.

17 Borody TJ, Andrews PJ, Brandl S, Hyland L, Morgan A,Ostapowicz N, et al. Endoscopic diagnosis of Helicobacterpylori (H pylori) - approaching the 'Gold Standard'.Abstracts ofthe World Congresses of Gastroenterology, Sydney,1990. Abingdon: The Medicine Group (UK) Ltd, 1990:PD91.

18 Hazell SL, Borody TJ, Gal A, Lee A. Campylobacter pylorigastritis. I: Detection of urease as a marker of bacterialcolonisation and gastritis. Am J Gastroenterol 1987; 82:292-6.

19 Borody T, Andrews P, Brandl S, Devine M. Relevance ofin-vitro metronidazole resistance to H pylori (HP) eradi-cation and eradication failure. Gastroenterology 1993; 104:A44.

20 Borody TJ, Brandl S, Andrews P, Ferch N, Jankiewicz E,Hyland L. Use of high efficacy, lower dose triple therapyto reduce side effects of eradicating Helicobacter pylori.Am Y Gastroenterol 1994; 89: 33-8.

21 Labenz J, Gyenes E, Ruhl GH, Borsch G. Omeprazole plusamoxycillin: efficacy of various treatment regimens toeradicate Helicobacter pylori. Am J Gastroenterol 1993;88: 491-5.

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23 Borody TJ, Andrews P, Mancuso N, Macauley D,Jankiewicz E, Ferch N, et al. Helicobacter pylori reinfec-tion rate, in patients with cured duodenal ulcer. Am JGastroenterol 1994; 89: 529-32.

24 Hosking SW, Ling TKW, Chung SCS, Yung MY, ChengAFB, Sung JJS, et al. Duodenal ulcer healing by eradica-tion of Helicobacter pylori without anti-acid treatment:randomised controlled trial. Lancet 1994; 343: 508-10.

25 Tucci A, Corinaldesi R, Stanghellini V, Paparo GF,Gasperoni S, Biasco G, et al. One-day therapy for treat-ment of Helicobacter pylori infection. Dig Dis Sci 1993;38: 1670-3.

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27 Thijs JC, Van Zwet AA, Oey HB. Efficacy and side effectsof a triple drug regimen for the eradication ofHelicobacterpylori. ScandJ7 Gastroenterol 1993; 28: 934-8.

28 Burette A, Glupczynski Y, De Prex C. Evaluation of variousmulti-drug eradication regimens for Helicobacter pylori.EurJ Gastroenterol Hepatol 1992; 4: 817-23.

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